ID   CEL2A_HUMAN             Reviewed;         269 AA.
AC   P08217; B2R5I4; Q14243;
DT   01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
DT   01-AUG-1988, sequence version 1.
DT   24-JAN-2024, entry version 190.
DE   RecName: Full=Chymotrypsin-like elastase family member 2A {ECO:0000305};
DE            EC=3.4.21.71;
DE   AltName: Full=Elastase-2A;
DE   Flags: Precursor;
GN   Name=CELA2A {ECO:0000312|HGNC:HGNC:24609}; Synonyms=ELA2A;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=3427074; DOI=10.1021/bi00397a010;
RA   Fletcher T.S., Shen W.F., Largman C.;
RT   "Primary structure of human pancreatic elastase 2 determined by sequence
RT   analysis of the cloned mRNA.";
RL   Biochemistry 26:7256-7261(1987).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=3646943; DOI=10.1089/dna.1987.6.163;
RA   Kawashima I., Tani T., Shimoda K., Takiguchi Y.;
RT   "Characterization of pancreatic elastase II cDNAs: two elastase II mRNAs
RT   are expressed in human pancreas.";
RL   DNA 6:163-172(1987).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Pancreas;
RX   PubMed=2834346; DOI=10.1093/oxfordjournals.jbchem.a122204;
RA   Shirasu Y., Yoshida H., Matsuki S., Takemura K., Ikeda N., Shimada Y.,
RA   Ozawa T., Mikayama T., Iijima H., Ishida A., Sato Y., Tamai Y., Tanaka J.,
RA   Ikenaga H.;
RT   "Molecular cloning and expression in Escherichia coli of a cDNA encoding
RT   human pancreatic elastase 2.";
RL   J. Biochem. 102:1555-1563(1987).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Pancreas, and Prostate;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16710414; DOI=10.1038/nature04727;
RA   Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA   Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA   Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA   Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA   Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA   Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA   Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA   Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA   Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA   Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA   Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA   Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA   Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA   Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA   Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA   Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA   Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA   Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA   McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA   Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA   Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA   Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA   Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA   Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA   White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA   Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA   Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA   Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT   "The DNA sequence and biological annotation of human chromosome 1.";
RL   Nature 441:315-321(2006).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Pancreas;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [8]
RP   PROTEIN SEQUENCE OF 18-50, AND INTERACTION WITH CPA1.
RX   PubMed=2307232; DOI=10.1016/0014-5793(90)80665-6;
RA   Moulard M., Michon T., Kerfelec B., Chapus C.;
RT   "Further studies on the human pancreatic binary complexes involving
RT   procarboxypeptidase A.";
RL   FEBS Lett. 261:179-183(1990).
RN   [9]
RP   TISSUE SPECIFICITY.
RX   PubMed=10620133; DOI=10.1046/j.1523-1747.2000.00825.x;
RA   Talas U., Dunlop J., Khalaf S., Leigh I.M., Kelsell D.P.;
RT   "Human elastase 1: evidence for expression in the skin and the
RT   identification of a frequent frameshift polymorphism.";
RL   J. Invest. Dermatol. 114:165-170(2000).
RN   [10]
RP   INVOLVEMENT IN AOMS4, FUNCTION, VARIANTS AOMS4 MET-70; MET-85 AND ASN-121,
RP   CHARACTERIZATION OF VARIANTS AOMS4 MET-70; MET-85 AND ASN-121, INTERACTION
RP   WITH SERPINA1, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX   PubMed=31358993; DOI=10.1038/s41588-019-0470-3;
RA   Esteghamat F., Broughton J.S., Smith E., Cardone R., Tyagi T., Guerra M.,
RA   Szabo A., Ugwu N., Mani M.V., Azari B., Kayingo G., Chung S., Fathzadeh M.,
RA   Weiss E., Bender J., Mane S., Lifton R.P., Adeniran A., Nathanson M.H.,
RA   Gorelick F.S., Hwa J., Sahin-Toth M., Belfort-DeAguiar R., Kibbey R.G.,
RA   Mani A.;
RT   "CELA2A mutations predispose to early-onset atherosclerosis and metabolic
RT   syndrome and affect plasma insulin and platelet activation.";
RL   Nat. Genet. 51:1233-1243(2019).
CC   -!- FUNCTION: Elastase that enhances insulin signaling and might have a
CC       physiologic role in cellular glucose metabolism. Circulates in plasma
CC       and reduces platelet hyperactivation, triggers both insulin secretion
CC       and degradation, and increases insulin sensitivity.
CC       {ECO:0000269|PubMed:31358993}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Preferential cleavage: Leu-|-Xaa, Met-|-Xaa and Phe-|-Xaa.
CC         Hydrolyzes elastin.; EC=3.4.21.71;
CC         Evidence={ECO:0000269|PubMed:31358993};
CC   -!- SUBUNIT: Interacts with CPA1. Interacts with SERPINA1
CC       (PubMed:31358993). {ECO:0000269|PubMed:2307232,
CC       ECO:0000269|PubMed:31358993}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:31358993}.
CC   -!- TISSUE SPECIFICITY: Expressed in pancreas. Not detected in
CC       keratinocytes (PubMed:10620133). Detected in exocrine secretions of the
CC       pancreas (at protein level). Also expressed in a small fraction of
CC       cells in pancreatic islets, adrenal cortex, intestinal glands and
CC       colonic lymphoid follicles (at protein level) (PubMed:31358993).
CC       Detected in plasma (PubMed:31358993). {ECO:0000269|PubMed:10620133,
CC       ECO:0000269|PubMed:31358993}.
CC   -!- DISEASE: Abdominal obesity-metabolic syndrome 4 (AOMS4) [MIM:618620]: A
CC       form of abdominal obesity-metabolic syndrome, a disorder characterized
CC       by abdominal obesity, high triglycerides, low levels of high density
CC       lipoprotein cholesterol, high blood pressure, and elevated fasting
CC       glucose levels. AOMS4 is an autosomal dominant disease. Patients
CC       manifest obesity, hypertension, early-onset coronary artery disease and
CC       type 2 diabetes. {ECO:0000269|PubMed:31358993}. Note=The disease is
CC       caused by variants affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the peptidase S1 family. Elastase subfamily.
CC       {ECO:0000255|PROSITE-ProRule:PRU00274}.
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DR   EMBL; M16631; AAA52374.1; -; mRNA.
DR   EMBL; M16652; AAA52380.1; -; mRNA.
DR   EMBL; D00236; BAA00165.1; -; mRNA.
DR   EMBL; AK312198; BAG35131.1; -; mRNA.
DR   EMBL; AK056678; BAG51782.1; -; mRNA.
DR   EMBL; AL512883; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471167; EAW51727.1; -; Genomic_DNA.
DR   EMBL; BC007031; AAH07031.1; -; mRNA.
DR   CCDS; CCDS157.1; -.
DR   PIR; B26823; B26823.
DR   RefSeq; NP_254275.1; NM_033440.2.
DR   AlphaFoldDB; P08217; -.
DR   SMR; P08217; -.
DR   BioGRID; 121962; 16.
DR   STRING; 9606.ENSP00000352639; -.
DR   DrugBank; DB06901; 2-(2-HYDROXY-CYCLOPENTYL)-PENT-4-ENAL.
DR   MEROPS; S01.155; -.
DR   iPTMnet; P08217; -.
DR   PhosphoSitePlus; P08217; -.
DR   BioMuta; CELA2A; -.
DR   DMDM; 119255; -.
DR   MassIVE; P08217; -.
DR   PaxDb; 9606-ENSP00000352639; -.
DR   PeptideAtlas; P08217; -.
DR   ProteomicsDB; 52086; -.
DR   Antibodypedia; 14313; 112 antibodies from 17 providers.
DR   DNASU; 63036; -.
DR   Ensembl; ENST00000359621.5; ENSP00000352639.4; ENSG00000142615.8.
DR   GeneID; 63036; -.
DR   KEGG; hsa:63036; -.
DR   MANE-Select; ENST00000359621.5; ENSP00000352639.4; NM_033440.3; NP_254275.1.
DR   UCSC; uc001awk.4; human.
DR   AGR; HGNC:24609; -.
DR   CTD; 63036; -.
DR   DisGeNET; 63036; -.
DR   GeneCards; CELA2A; -.
DR   HGNC; HGNC:24609; CELA2A.
DR   HPA; ENSG00000142615; Tissue enriched (pancreas).
DR   MalaCards; CELA2A; -.
DR   MIM; 609443; gene.
DR   MIM; 618620; phenotype.
DR   neXtProt; NX_P08217; -.
DR   OpenTargets; ENSG00000142615; -.
DR   PharmGKB; PA165750794; -.
DR   VEuPathDB; HostDB:ENSG00000142615; -.
DR   eggNOG; KOG3627; Eukaryota.
DR   GeneTree; ENSGT01030000234528; -.
DR   HOGENOM; CLU_006842_0_4_1; -.
DR   InParanoid; P08217; -.
DR   OMA; GSTLGCN; -.
DR   OrthoDB; 4629979at2759; -.
DR   PhylomeDB; P08217; -.
DR   TreeFam; TF330455; -.
DR   PathwayCommons; P08217; -.
DR   Reactome; R-HSA-6809371; Formation of the cornified envelope.
DR   BioGRID-ORCS; 63036; 11 hits in 1145 CRISPR screens.
DR   GeneWiki; CELA2A; -.
DR   GenomeRNAi; 63036; -.
DR   Pharos; P08217; Tbio.
DR   PRO; PR:P08217; -.
DR   Proteomes; UP000005640; Chromosome 1.
DR   RNAct; P08217; Protein.
DR   Bgee; ENSG00000142615; Expressed in body of pancreas and 92 other cell types or tissues.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR   GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR   GO; GO:0036457; C:keratohyalin granule; IDA:MGI.
DR   GO; GO:0004175; F:endopeptidase activity; IDA:UniProtKB.
DR   GO; GO:0017171; F:serine hydrolase activity; IDA:MGI.
DR   GO; GO:0004252; F:serine-type endopeptidase activity; IBA:GO_Central.
DR   GO; GO:1901143; P:insulin catabolic process; IDA:UniProtKB.
DR   GO; GO:0006508; P:proteolysis; IBA:GO_Central.
DR   GO; GO:0050796; P:regulation of insulin secretion; IDA:UniProtKB.
DR   GO; GO:0090330; P:regulation of platelet aggregation; IDA:UniProtKB.
DR   GO; GO:0032868; P:response to insulin; IDA:UniProtKB.
DR   CDD; cd00190; Tryp_SPc; 1.
DR   Gene3D; 2.40.10.10; Trypsin-like serine proteases; 2.
DR   InterPro; IPR009003; Peptidase_S1_PA.
DR   InterPro; IPR043504; Peptidase_S1_PA_chymotrypsin.
DR   InterPro; IPR001314; Peptidase_S1A.
DR   InterPro; IPR001254; Trypsin_dom.
DR   InterPro; IPR018114; TRYPSIN_HIS.
DR   InterPro; IPR033116; TRYPSIN_SER.
DR   PANTHER; PTHR24257; CHYMOTRYPSIN-LIKE ELASTASE FAMILY MEMBER; 1.
DR   PANTHER; PTHR24257:SF24; CHYMOTRYPSIN-LIKE ELASTASE FAMILY MEMBER 2A; 1.
DR   Pfam; PF00089; Trypsin; 1.
DR   PRINTS; PR00722; CHYMOTRYPSIN.
DR   SMART; SM00020; Tryp_SPc; 1.
DR   SUPFAM; SSF50494; Trypsin-like serine proteases; 1.
DR   PROSITE; PS50240; TRYPSIN_DOM; 1.
DR   PROSITE; PS00134; TRYPSIN_HIS; 1.
DR   PROSITE; PS00135; TRYPSIN_SER; 1.
DR   Genevisible; P08217; HS.
PE   1: Evidence at protein level;
KW   Diabetes mellitus; Direct protein sequencing; Disease variant;
KW   Disulfide bond; Hydrolase; Obesity; Protease; Reference proteome; Secreted;
KW   Serine protease; Signal; Zymogen.
FT   SIGNAL          1..16
FT   PROPEP          17..28
FT                   /note="Activation peptide"
FT                   /id="PRO_0000027693"
FT   CHAIN           29..269
FT                   /note="Chymotrypsin-like elastase family member 2A"
FT                   /id="PRO_0000027694"
FT   DOMAIN          29..267
FT                   /note="Peptidase S1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00274"
FT   ACT_SITE        73
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        121
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        216
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000250"
FT   DISULFID        58..74
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00274"
FT   DISULFID        155..222
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00274"
FT   DISULFID        186..202
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00274"
FT   DISULFID        212..243
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00274"
FT   VARIANT         70
FT                   /note="T -> M (in AOMS4; strongly decreased elastase
FT                   activity; abolishes interaction with SERPINA1; impaired
FT                   insulin degradation; increased platelet aggregation;
FT                   dbSNP:rs372947070)"
FT                   /evidence="ECO:0000269|PubMed:31358993"
FT                   /id="VAR_083326"
FT   VARIANT         85
FT                   /note="L -> M (in AOMS4; uncertain significance; strongly
FT                   decreased elastase activity; no effect on interaction with
FT                   SERPINA1; no effect on insulin degradation; increased
FT                   platelet aggregation; dbSNP:rs558493952)"
FT                   /evidence="ECO:0000269|PubMed:31358993"
FT                   /id="VAR_083327"
FT   VARIANT         121
FT                   /note="D -> N (in AOMS4; strongly decreased elastase
FT                   activity; abolishes interaction with SERPINA1; increased
FT                   levels in plasma; impaired insulin degradation; increased
FT                   platelet aggregation; dbSNP:rs1352544800)"
FT                   /evidence="ECO:0000269|PubMed:31358993"
FT                   /id="VAR_083328"
FT   VARIANT         257
FT                   /note="N -> S (in dbSNP:rs2303193)"
FT                   /id="VAR_051837"
FT   CONFLICT        202
FT                   /note="C -> V (in Ref. 3; BAA00165)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   269 AA;  28888 MW;  A2E05143EFF4987C CRC64;
     MIRTLLLSTL VAGALSCGDP TYPPYVTRVV GGEEARPNSW PWQVSLQYSS NGKWYHTCGG
     SLIANSWVLT AAHCISSSRT YRVGLGRHNL YVAESGSLAV SVSKIVVHKD WNSNQISKGN
     DIALLKLANP VSLTDKIQLA CLPPAGTILP NNYPCYVTGW GRLQTNGAVP DVLQQGRLLV
     VDYATCSSSA WWGSSVKTSM ICAGGDGVIS SCNGDSGGPL NCQASDGRWQ VHGIVSFGSR
     LGCNYYHKPS VFTRVSNYID WINSVIANN
//